Recent advances in genomic and proteomic research have opened new vistas for identifying specific molecular markers of disease. In order to exploit these markers for biomedical imaging, high affinity ligands are urgently needed. Frequently, however, monovalent ligands for molecular markers lack the affinity needed for efficient targeting in vivo. Recently, multivalent drug design has been shown to increase affinity by several orders of magnitude (Angew Chem 1998;37:2754-2794). The goal of this proposal is to develop and test novel approaches for the efficient, parallel synthesis and high throughput screening of multivalent, molecularly targeted MR imaging agents. The underlying hypothesis of the proposed research is that multivalency can be utilized to obtain the affinity and specificity needed for in vivo imaging of molecular markers. Magnetic nanoparticles are an ideal platform for the development of new synthetic and screening methods for multivalent imaging agents because (i) the uptake of nanoparticles by cells, and resulting changes in relaxation rate, can be analyzed in a high throughput fashion by MRI, (ii) recent advances in conjugation chemistry allow the attachment of low molecular weight ligands nanoparticles with widely varying valencies, (iii) magnetic nanoparticles are non-toxic and amenable to clinical development, (iv) because magnetic nanoparticles are highly detectable by MR The specific aims of this proposal include systematic synthesis of positionally encoded, multivalent peptide-nanoparticle libraries. Using different read-out methods we will also investigate high throughput screening techniques and validate these approaches. We hypothesize that i) large numbers of peptidenanoparticle conjugates can be created with a miniaturized, parallel synthesis and screened in high through put fashion, ii) that multivalency and linker arm chemistry will play an important role in determining the affinity nanoparticles exhibit for cellular targets, and iii) that MR agents thus developed as probes for activated endothelial cells will expand our capabilities to image the endothelium in a variety of important pathological states. The planned research will provide critical technology and enable the rapid development of molecularly targeted imaging agents.